Base excision repair (BER) is one of the major cellular DNA repair pathways that repairs small isolated foci of DNA damage including reduced or oxidized single bases or fragments and small, non-bulky adducts. Genetic variations in BER genes may affect DNA repair capacity and increase susceptibility to bladder cancer. In a case–control study of 801 bladder cancer patients and 801 matched controls, we evaluated the associations of 167 single nucleotide polymorphisms (SNPs) from 19 genes of the BER pathway with the risk of bladder cancer. In individual SNP analysis, 13 SNPs in 10 BER pathway genes were significantly associated with bladder cancer risk. The most significant SNP was rs2029167 in the SMUG1 gene. The homozygous variant GG genotype was associated with a 1.42-fold increased risk of bladder cancer (95% confidence interval [CI], 1.11–1.82, P = 0.005). Cumulative effect analysis showed joint effects of increased risk of bladder cancer with increasing number of unfavorable genotypes in patients. Classification and regression tree analysis further revealed high-order gene–gene interactions and categorized the study subjects into low-, medium–low-, medium–high-, and high-risk groups. Compared with the low-risk group, the odds ratio for medium–low-, medium–high-, and high-risk group was 1.83 (95% CI: 1.23–2.72), 2.61 (95% CI: 1.79–3.80), and 3.05 (95% CI: 2.08–4.46), respectively (P for trend <0.001). Our results suggest that genetic variations in BER pathway genes modulate the risk of bladder cancer individually and jointly. © 2013 Wiley Periodicals, Inc.